This invention concerns a novel chemical process, and more particularly it concerns a novel chemical process for the manufacture of tert-butyl (E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl}(4R,6S)-2,2dimethyl[1,3]dioxan-4-yl)acetate of formula I, 
(hereinafter referred to as BEM) which is useful, for example, as a chemical intermediate in the production of a pharmaceutical useful in the treatment of, inter alia, hypercholesterolemia, hyperlipoproteinemia and atherosclerosis. The invention further includes the novel starting material used in said process and the use of the process in the manufacture of an HMG CoA reductase inhibitor.
In European Patent Application, Publication No. (EPA) 0521471 is disclosed (E)-7-[4(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5dihydroxyhept 6-enoic acid and its sodium salt and calcium salt (illustrated below) 
(hereinafter referred to collectively as xe2x80x9cThe Agentxe2x80x9d) as inibitors of HMG CoA reductase. The Agent is obtained therein via reduction of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl-amino)pyrimidin-5-yl-(3R)-3-hydroxy-5-oxo-(E)-heptenoate and subsequent processing. However the Agent may be obtained from BEM by treatment with acid (to cleave the acetonide protecting group) followed by base (to cleave the ester) and (as described in EPA 0521471) conversion of the initially formed salt to the free acid or the calcium salt.
We have now discovered a useful and advantageous process for preparing BEM.
According to the invention there is provided a process for preparing BEM (formula I) which comprises reaction of diphenyl [4-(4-fluoropheny)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl] phosphine oxide of formula III 
(hereinafter referred to as DPPO) with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl}acetate of formula II 
(hereinafter referred to as BFA) in the presence of a strong base.
The process is carried out in a suitable solvent, or mixture of solvents for example, ethereal or aromatic solvents or mixtures thereof. Particularly suitable solvents include, for example, tetrahydrofuran (THF), dimethoxyethane and toluene, or mixtures thereof. Particularly preferred solvents include, for example, THF and THF and toluene.
Suitable bases for use in the process include, for example, amide bases, alkyl metals and metal hydrides. Particular bases include, for example, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethysilyl)amide, butyllithium and sodium hydride. A particularly preferred base is, for example, sodium bis(trimethylsilyl)amide (NaHMDS).
The reaction may be carried out at a temperature in the range of, for example, xe2x88x9220xc2x0 C. to xe2x88x9290xc2x0 C., such as xe2x88x9240xc2x0 C. to xe2x88x9290xc2x0 C., for example xe2x88x9240xc2x0 C. to xe2x88x9280xc2x0 C. A convenient tempreture at which to carry out the reaction is, for example, that of a mixture of acetone and solid carbon dioxide (about xe2x88x9275xc2x0 C.).
The process is advantageously carried out with 1.0 to 1.2 equivalents of base (per equivalent of DPPO), such as 1.05 to 1.2 equivalents and preferably 1.05 to 1.12 equivalents. Although BFA can be present in large excess, it is convenient to use 1.0 to 1.35 equivalents (per equivalent of DPPO), and preferably 1.05 to 1.3 equivalents, especially 1.05 to 1.15 equivalents.
The process of the invention provides significantly improved yields and quality of product by comparison to when a corresponding dialkyl phosphonate (xe2x80x94PO(Oalkyl)2) starting material is used instead of DPPO.
The starting material, DPPO, which is a further aspect of the present invention, may be obtained as described in the Examples hereinafter, starting from an alkyl 2-amino-4-(4-fluorophenyl)-6-isopropylpyrimidin-5-carboxylate, for example the methyl ester which may be obtained as described in Japanese Patent Application No. 06-256318, or the ethyl ester which may be obtained as described in EPA 0521471. BFA may be obtained as described in EPA 0319847 (Example 6).
A further aspect of the present invention is a process for the manufacture of a compound of the formula IV 
in which R1 is hydrogen or a pharmaceutically acceptable cation, which comprises;
(1) reaction of DPPO with BFA in the presence of a strong base (as described above) to give BEM;
(2) cleavage of the dihydroxy (acetonide) protecting group (for example by acid hydrolysis, such as by using HCl in THF or acetonitrile); and
(3) cleavage of the tert-butyl ester group under basic conditions to form a compound of the formula IV in which R1 is a pharmaceutically acceptable cation (for example by using a solution of a metallic hydroxide in a polar solvent, such as using aqueous sodium hydroxide in ethanol or acetonitrile to form the sodium salt);
optionally followed by neutralisation to give a compound of the formula IV in which R1 is hydrogen;
and/or optionally followed by conversion to another compound of the formula IV in which R1 is a pharmaceutically acceptable cation (for example conversion of the sodium salt to the calcium salt by treatment with a water soluble calcium salt (such as calcium chloride) under aqueous conditions).
Suitable conditions for steps (2), (3) and the subsequent optional steps are analogous to, or the same as, those disclosed in EPA 0521471 and/or EPA 0319847, which are hereby incorporated herein by reference. To obtain the calcium salt of the compound of formula IV, as illustrated on page 1, preferably steps (2), (3) and conversion to the calcium salt via the methylamine salt are carried out as described in Example 7, which steps form a further aspect of the invention.
It will be appreciated that, in the processes described above, BFA may replaced by a compound of the general formula V 
in which P3 is a carboxylic acid protecting group, for example (1-8C)alkyl (such as 1-4C)alkyl), and P1 and P2 are alcohol protecting groups, or P1 and P2 taken together is a 1 , 3-diol protecting group, such as those described in EPA 0319845 and GB 2244705 which are included herein by reference. For example, in some preferred embodiments, the 1,3-dial protecting groups can be 
where R1 and R2 are independently (1-4C)alkyl or R1 and R2, taken together with the carbon atom to which they are attached, form a cyclopentyl. cyclohexyl or cycloheptyl ring. Reaction of a compound of the formula V with a compound of the formula III forms a compound of the formula VI 
The compound of the formula VI may be converted to the Agent by cleavage of the alcohol or diol protecting groups and conversion of the COOP3 to a COOH group or a pharmaceutically acceptable salt thereof. Such general processes form further features of the present invention.
The invention if further illustrated, but not limited by the following Examples.
Preparation 1
Preparation of DPPO
A stirred mixture of methyl 4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-carboxylate (12.0 g) in toluene (55 ml) was cooled to xe2x88x9210xc2x0 C. and diisobutyl aluminium hydride (50 ml of a 1.5M solution in toluene) was added over two hours maintaining the temperature below 0xc2x0 C. After addition, the mixture was stirred for 30 minutes at 0xc2x0 C. Methanol (0.64 ml) was added to the mixture maintaining the temperature at 0xc2x0 C. The mixture was then added over two hours to a stirred mixture of concentrated hydrochloric acid (23.3 ml), water (40.5 ml) and acetonitrile (24 ml) at 40xc2x0 C., maintaining the temperature of the mixture at 40xc2x0 C. After addition, the mixture was stirred at 40xc2x0 C. for a further 30 minutes and then purged with nitrogen (to remove any isobutane). The mixture was cooled to 20xc2x0 C. and allowed to stand for 20 minutes. The organic phase was separated and washed with a mixture of concentrated hydrochloric acid (0.7 ml) and water (30 ml). Acetonitrile (24 ml) was added to the organic phase and the mixture washed with a solution of sodium bicarbonate (0.038 g) in water (120 ml).
The organic phase was heated to 40xc2x0 C., and then from 40xc2x0 C. to 80xc2x0 C. using a nitrogen purge. The mixture was concentrated by distillation at atmospheric pressure, collecting 54 ml of distillate. Acetonitrile (24 ml) was added to the concentrated solution and phosphorus tribromide (1.2 ml) was added with stirring, maintaining the temperature of the mixture at 20xc2x0 C. After addition, the mixture was stirred at 20xc2x0 C. for 30 minutes. The mixture was added to water (36 ml) over 30 minutes maintaining the temperature at 20xc2x0 C. The mixture was stirred for 5 minutes and the organic phase separated. The organic phase was washed with a solution of sodium bicarbonate (0.027 g) in water (36 ml), followed by water (36 ml). The organic phase was distilled under reduced pressure until 29 ml of distillates was collected. The mixture was cooled to 60xc2x0 C. and ethyl diphenylphosphinite (7.47 ml) was added. The mixture was stirred at 60xc2x0 C. for 3 hours, then heated to reflux. Toluene (40 ml) was added and the mixture cooled to 0xc2x0 C. over 2 hours. The product was collected by filtration, washed with cold toluene (10 ml) and dried under vacuum at 50xc2x0 C. to give DPPO (14.66 g); 1HNMR (CDCl3, 270 MHz): 7.42 [m, 10H, P(C6H5)2], 7.12 [m, 2H, Arxe2x80x94H], 6.92 [m, [d,2H, CH2P], 3.51, 3.46 (2xc3x97 s, 6H, NCH, SO2CH3], 3.43 [hept., 1H, CH(CH3)2],1.25[d, 6H, CH(CH3)2],1.25[d,6H, CH(CH3)2]
Methyl 4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino)pyrimidine-5-carboxylate was prepared as follows:
A mixture of methyl 2-amino-4-(4-fluorophenyl)-6-isopropyl-pyrimidine-5-carboxylate (19.0 g), sodium tert-pentoxide (22.95 g) and dimethoxyethane (190 ml) was stirred for 30 minutes at 25xc2x0 C. The stirred mixture was cooled to xe2x88x9210xc2x0 C. and methanesulfonyl chloride (8.4 ml) was added dropwise, maintaining the temperature of the mixture at xe2x88x925xc2x0 C. After 20 minutes, dimethyl sulfate (8.1 ml) was added and the mixture allowed to warm to 25xc2x0 C. The mixture was stirred for one hour at 25xc2x0 C. and a solution of sodium tert-pentoxide (1.91 g) in dimethoxyethane (10 ml) added. The mixture was stirred for one hour at 25xc2x0 C. A solution of sodium chloride (13.3 g) in water (133 ml) was added and the mixture was stirred for 10 minutes at 25xc2x0 C. The mixture was allowed to settle for 15 minutes and the lower aqueous phase was separated and discarded. Water (38 ml) was added to the remaining mixture and the mixture was stirred for 30 minutes at 25xc2x0 C. The mixture was then heated to obtain a complete solution. The mixture was cooled slowly to 25xc2x0 C. over one hour. The mixture was cooled to 0xc2x0 C., stirred for one hour, and the suspended solid collected by filtration. The solid was washed with cold (0xc2x0 C.) solution of 50:50 water/dimethoxyethane (20 ml). The solid was dried under vacuum at 60xc2x0 C. to give methyl 4-(4-fluorophenyl)-6isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidine-5-carboxylate (19.35 g); 1HNMR (270 MHz, CDCl3): 7.69 (m,2H), 7.14 (m,2H), 3.71, 3.60, 3.51(3xc3x97 s, 9H), 3.20 (m, 1.(d,6H).